Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Jun;28(1-2):51-63.
doi: 10.1007/s10555-008-9168-1.

Pak protein kinases and their role in cancer

Bettina Dummler  1 , Kazufumi Ohshiro, Rakesh Kumar, Jeffrey Field
Affiliations
Review

Pak protein kinases and their role in cancer

Bettina Dummler et al. Cancer Metastasis Rev. 2009 Jun.

Abstract

Some of the characteristics of cancer cells are high rates of cell proliferation, cell survival, and the ability to invade surrounding tissue. The cytoskeleton has an essential role in these processes. Dynamic changes in the cytoskeleton are necessary for cell motility and cancer cells are dependent on motility for invasion and metastasis. The signaling pathways behind the reshaping and migrating properties of the cytoskeleton in cancer cells involve a group of Ras-related small GTPases and their effectors, including the p21-activated kinases (Paks). Paks are a family of serine/threonine protein kinases comprised of six isoforms (Pak 1-6), all of which are direct targets of the small GTPases Rac and Cdc42. Besides their role in cytoskeletal dynamics, Paks have recently been shown to regulate various other cellular activities, including cell survival, mitosis, and transcription. Paks are overexpressed and/or hyperactivated in several human tumors and their role in cell transformation makes them attractive therapeutic targets. Pak-targeted therapeutics may efficiently inhibit certain types of tumors and efforts to identify selective Pak-inhibitors are underway.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Domain structure of Pak isoforms. The p21 (Rac/Cd42)-binding domain (PBD) and kinase domain are shown, as well as proline-rich putative SH3-binding motifs. Groups I Paks additionally contain an autoinhibitory domain (PID) that is overlapping with the PBD
Fig. 2
Fig. 2
Schematic diagram of Pak activation by the small GTPases Rac and Cdc42. Signals from receptor tyrosine kinases, (e.g. insulin, EGF, PDGF, and VEGF receptors) and G protein-coupled receptors lead to activation of Pak via GTP-bound Rac and Cdc42. Activated Pak in turn initiates signaling cascades that culminate in the cellular response. In addition, activated Pak potentiates activation of the MAP kinase pathway. Of note, while activation of Pak via Rac and Cdc42 is well characterized, a number of GTPase-independent mechanisms for Pak activation have also been identified. GPCR, G protein-coupled receptors; RTK, receptor tyrosine kinase; PI3 K, phosphatidylinositol-3 kinase; PIP3, phosphatidylinositol (3, 4, 5) trisphosphate
See this image and copyright information in PMC

References

    1. Manser E, et al. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994;367:40–46. - PubMed
    1. Tahara SM, Traugh JA. Cyclic Nucleotide-independent protein kinases from rabbit reticulocytes. Identification and characterization of a protein kinase activated by proteolysis. Journal of Biological Chemistry. 1981;256(22):11558–11564. - PubMed
    1. Bokoch GM. Biology of the p21-activated kinases. Annu. Rev. Biochem. 2003;72:743–781. - PubMed
    1. Jaffer ZM, Chernoff J. p21-activated kinases: three more join the Pak. International Journal of Ciochemistry and Cell Biology. 2002;34(7):713–717. - PubMed
    1. Zhao Z, et al. A conserved Negative Regulatory Region in aPAK: inhibition of PAK Kinases Reveals Their Morphological Roles Downstream of Cdc42 and Rac1. Molecular and Cell Biology. 1998;18(4):2153–2163. - PMC - PubMed

Publication types